Information about the specific regulatory environment of orphan drugs is scarce and inconsistent. Uncertainties surrounding the postmarketing long-term safety of orphan drugs remain. This study aimed ...to evaluate the labelling changes of orphan drugs and to identify postmarketing safety-associated approval factors.
This retrospective cohort study includes all drugs with orphan drug designation approved by the Center for Drug Evaluation and Research of the US Food and Drug Administration between 1999 and 2018. Main outcomes are safety-related labelling changes up to 31 December 2019. We defined any safety-related labelling changes as postmarketing safety events (PMSE). Safety-related withdrawals, suspensions, and boxed warnings were further categorised as severe postmarketing safety events (SPSE). Outcome measurements include frequencies of PMSE, SPSE, and association between approval factors and the occurrence of safety events.
Amongst the 214 drugs identified with orphan drug designation (25.7% biologics), 83.6% were approved through at least one expedited programme, and 29.4% were approved with boxed warnings. During a median follow-up of 6.74 years since approval, 69.2% and 14.5% of the analysed orphan drugs had PMSE and SPSE, respectively. Safety-related withdrawal (0%, 0/214), suspended marketing (0.46%, 1/214) and new boxed warnings are uncommon (3.7%, 8/214). The safety-related labelling changes were more frequent in the drugs approved with boxed warnings Incidence rate ratio (IRR): 1.95 (1.02-3.73) and approved for long-term use IRR: 2.76 (1.52-5.00).
In this long-term postmarketing analysis, approximately 70% of FDA-approved orphan drugs had safety-related labelling changes although severe safety events were rare. While maintaining early access to orphan drugs, the drug regulatory body has taken timely regulatory action with postmarketing surveillance to ensure patient safety.
Understanding demographic difference in facial expression of happiness has crucial implications on social communication. However, prior research on facial emotion expression has mostly focused on the ...effect of a single demographic factor (typically gender, race, or age), and is limited by the small image dataset collected in laboratory settings. First, we used 30,000 (4800 after pre-processing) real-world facial images from Flickr, to analyze the facial expression of happiness as indicated by the intensity level of two distinctive facial action units, the Cheek Raiser (AU6) and the Lip Corner Puller (AU12), obtained automatically via a deep learning algorithm that we developed, after training on 75,000 images. Second, we conducted a statistical analysis on the intensity level of happiness, with both the main effect and the interaction effect of three core demographic factors on AU12 and AU6. Our results show that females generally display a higher AU12 intensity than males. African Americans tend to exhibit a higher AU6 and AU12 intensity, when compared with Caucasians and Asians. The older age groups, especially the 40-69-year-old, generally display a stronger AU12 intensity than the 0-3-year-old group. Our interdisciplinary study provides a better generalization and a deeper understanding on how different gender, race and age groups express the emotion of happiness differently.
Tuning the threshold voltage of a transistor is crucial for realizing robust digital circuits. For silicon transistors, the threshold voltage can be accurately controlled by doping. However, it ...remains challenging to tune the threshold voltage of single-wall nanotube (SWNT) thin-film transistors. Here, we report a facile method to controllably n-dope SWNTs using 1 H -benzoimidazole derivatives processed via either solution coating or vacuum deposition. The threshold voltages of our polythiophene-sorted SWNT thin-film transistors can be tuned accurately and continuously over a wide range. Photoelectron spectroscopy measurements confirmed that the SWNT Fermi level shifted to the conduction band edge with increasing doping concentration. Using this doping approach, we proceeded to fabricate SWNT complementary inverters by inkjet printing of the dopants. We observed an unprecedented noise margin of 28 V at V DD = 80 V (70% of 1/2 V DD) and a gain of 85. Additionally, robust SWNT complementary metal−oxide−semiconductor inverter (noise margin 72% of 1/2 V DD) and logic gates with rail-to-rail output voltage swing and subnanowatt power consumption were fabricated onto a highly flexible substrate.
Beijing is one of the most polluted cities in the world. However, the “Air Pollution Prevention and Control Action Plan” (APPCAP), introduced since 2013 in China, has created an unprecedented drop in ...pollution concentrations for five major pollutants, except O3, with a significant drop in mortalities across most parts of the city. To assess the effects of APPCAP, air pollution data were collected from 35 sites (divided into four types, namely, urban, suburban, regional background, and traffic) in Beijing, from 2014 to 2018 and analyzed. Simultaneously, health-risk based air quality index (HAQI) and district-specific pollution (PM2.5 and O3) attributed mortality were calculated for Beijing. The results show that the annual PM2.5 concentration exceeded the Chinese national ambient air quality standard Grade II (35 μg/m3) in all sites, ranging from 88.5 ± 77.4 μg/m3 for the suburban site to 98.6 ± 89.0 μg/m3 for the traffic site in 2014, but was reduced to 50.6 ± 46.6 μg/m3 for the suburban site, and 56.1 ± 47.0 μg/m3 for the regional background in 2018. O3 was another most important pollutant that exceeded the Grade II standard (160 μg/m3) for a total of 291 days. It peaked at 311.6 μg/m3 in 2014 for the urban site and 290.6 μg/m3 in 2018 in the suburban site. APPCAP led to a significant reduction in PM2.5, PM10, NO2, SO2 and CO concentrations by 7.4, 8.1, 2.4, 1.9 and 80 μg/m3/year respectively, though O3 concentration was increased by 1.3 μg/m3/year during the five-years. HAQI results suggest that during the high pollution days, the more vulnerable groups, such as the children, and the elderly, should take additional precautions, beyond the recommendations currently put forward by Beijing Municipal Environmental Monitoring Center (BJMEMC). In 2014, PM2.5 and O3 attributed to 29,270 and 3,030 deaths respectively, though in 2018 their mortalities were reduced by 5.6% and 18.5% respectively. The highest mortality was observed in Haidian and Chaoyang districts, two of the most densely populated areas in Beijing. Beijing’s air quality has seen a dramatic improvement over the five-year period, which can be attributable to the implementation of APPCAP and the central government’s determination, with significant drops in the mortalities due to PM2.5 and O3 in parallel. To further improve air quality in Beijing, more stringent regulatory measures should be introduced to control volatile organic compounds (VOCs) and reduce O3 concentrations. Consistent air pollution control interventions will be needed to ensure long-term prosperity and environmental sustainability in Beijing, China’s most powerful city. This study provides a robust methodology for analyzing air pollution trends, health risks and mortalities in China. The crucial evidence generated forms the basis for the governments in China to introduce location-specific air pollution policy interventions to further reduce air pollution in Beijing and other parts of China. The methodology presented in this study can form the basis for future fine-grained air pollution and health risk study at the city-district level in China.
(Top) Time series data of air pollution in four regions in Beijing from 2014 to 2018. (Middle) Trend analysis of deseasonalised time series data. (Bottom) District specific premature death attributed to air pollution Display omitted
•Five years long criteria air pollutants data in Beijing were analyzed.•The significant reduction of PM2.5, PM10, NO2, SO2 and CO (7.4, 8.1, 2.4, 1.9 and 80 μg/m3/year).•O3 concentration increased (1.3 μg/m3/year) during the time frame.•HAQI results suggest that in high pollution days, the sensitive population groups such as children and the elderly should take more stringent.•From 2014 to 2018, PM2.5 and O3 attributed total deaths were decreased by 5.6% and 18.5%.
Collisionless shocks can be produced as a result of strong magnetic fields in a plasma flow, and therefore are common in many astrophysical systems. The Weibel instability is one candidate mechanism ...for the generation of sufficiently strong fields to create a collisionless shock. Despite their crucial role in astrophysical systems, observation of the magnetic fields produced by Weibel instabilities in experiments has been challenging. Using a proton probe to directly image electromagnetic fields, we present evidence of Weibel-generated magnetic fields that grow in opposing, initially unmagnetized plasma flows from laser-driven laboratory experiments. Three-dimensional particle-in-cell simulations reveal that the instability efficiently extracts energy from the plasma flows, and that the self-generated magnetic energy reaches a few percent of the total energy in the system. This result demonstrates an experimental platform suitable for the investigation of a wide range of astrophysical phenomena, including collisionless shock formation in supernova remnants, large-scale magnetic field amplification, and the radiation signature from gamma-ray bursts.
Critical factors that determine the percolation threshold of carbon nanotube (CNT)‐reinforced polymer nanocomposites are studied. An improved analytical model is developed based on an interparticle ...distance concept. Two dispersion parameters are introduced in the model to correctly reflect the different dispersion states of CNTs in the matrix—entangled bundles and well‐dispersed individual CNTs. CNT–epoxy nanocomposites with different dispersion states are fabricated from the same constituent materials by employing different processing conditions. The corresponding percolation thresholds of the nanocomposites vary over a wide range, from 0.1 to greater than 1.0 wt %, and these variations are explained in terms of dispersion parameters and aspect ratios of CNTs. Important factors that control the percolation threshold of nanocomposites are identified based on the comparison between modeling data and experimental results.
Experiments and modeling are used to study the effect of carbon nanotube (CNT) dispersions and aspect ratios on the percolation threshold of CNT–polymer nanocomposites. Four different processing conditions are used to achieve mixtures of individual CNTs and entangled bundles (see figure), and their electrical properties are characterized.
1ES 1927+654 is a nearby active galactic nucleus (AGN) that underwent a changing-look event in early 2018, developing prominent broad Balmer lines that were absent in previous observations. We have ...followed up this object in the X-rays with an ongoing campaign that started in 2018 May and that includes 265 NICER (for a total of 678 ks) and 14 Swift/XRT (26 ks) observations, as well as three simultaneous XMM-Newton/NuSTAR (158/169 ks) exposures. In the X-rays, 1ES 1927+654 shows a behavior unlike any previously known AGN. The source is extremely variable both in spectral shape and flux and does not show any correlation between X-ray and UV flux on timescales of hours or weeks/months. After the outburst, the power-law component almost completely disappeared, and the source showed an extremely soft continuum dominated by a blackbody component. The temperature of the blackbody increases with the luminosity, going from kT∼80 eV (for a 0.3–2 keV luminosity ofL0.3−2∼1041.5erg s−1) to∼200 eV (forL0.3−2∼1044erg s−1). The spectra show evidence of ionized outflows and of a prominent feature at ∼1 keV, which can be reproduced by a broad emission line. The unique characteristics of1ES 1927+654 in the X-ray band suggest that it belongs to a new type of changing-look AGN. Future X-ray surveys might detect several more objects with similar properties.
Archean cratons have map patterns and rock associations that are diagnostic of the Wilson Cycle. The North China Craton (NCC) consists of several distinctly different tectonic units, but the ...delineation and understanding of the significance of individual sutures and the rocks between them has been controversial. We present an actualistic tectonic division and evolution of the North China Craton based on Wilson Cycle and comparative tectonic analysis that uses a multi-disciplinary approach in order to define sutures, their ages, and the nature of the rocks between them, to determine their mode of formation and means of accretion or exhumation, and propose appropriate modern analogues. The eastern unit of the craton consists of several different small blocks assembled between 2.6 and 2.7Ga ago, that resemble fragments of accreted arcs from an assembled archipelago similar to those in the extant SW Pacific. A thick Atlantic-type passive margin developed on the western side of the newly assembled Eastern Block by 2.6–2.5Ga. A >1300km-long arc and accretionary prism collided with the margin of the Eastern Block at 2.5Ga, obducting ophiolites and ophiolitic mélanges onto the block, and depositing a thick clastic wedge in a foreland basin farther into the Eastern Block. This was followed by an arc-polarity reversal, which led to a short-lived injection of mantle wedge-derived melts to the base of the crust that led to the intrusion of mafic dikes and arc-type granitoid (TTG) plutons with associated metamorphism. By 2.43Ga, the remaining open ocean west of the accreted arc closed with the collision of an oceanic plateau now preserved as the Western Block with the collision-modified margin of the Eastern Block, causing further deformation in the Central Orogenic Belt. 2.4–2.35Ga rifting of the newly amalgamated continental block formed a rift along its center, and new oceans within the other two rift arms, which removed a still-unknown continental fragment from its northern margin. By 2.3Ga an arc collided with a new Atlantic-type margin developed over the rift sequence along the northern margin of the craton, and thus was converted to an Andean margin through arc-polarity reversal.
Andean margin tectonics affected much of the continental block from 2.3 to 1.9Ga, giving rise to a broad E-W swath of continental margin magmas, and retro-arc sedimentary basins including a foreland basin superimposed on the passive northern margin. The horizontal extent of these tectonic components is similar to that across the present-day Andes in South America. From 1.88 to 1.79Ga a granulite facies metamorphic event was superimposed across the entire continental block with high-pressure granulites and eclogites in the north, and medium-pressure granulites across the whole craton to the south. The scale and duration of this post-collisional event is similar to that in Central Asia that resulted from the Cenozoic India-Asia collision. The deep crustal granulites and volcanic rocks on the surface today, interpreted to be anatectic melts from deep crustal granulites, are similar to high-grade metamorphic rocks and partial melts presently forming at mid-crustal levels beneath Tibet. Structural fabrics in lower-crustal migmatites related to this event reveal that they flowed laterally parallel to the collision boundary, in a way comparable to what is speculated to be happening in the deep crust of the Himalayan/Tibetan foreland. We relate this continent-continent collision to the collision of the North China Craton with the postulated Columbia (Nuna) Continent. The NCC broke out of the Columbia Continent between 1753–1673Ma, as shown by the formation of a suite of anorthosite, mangerite, charnockite, and alkali-feldspar granites in an ENE-striking belt along the northern margin of the craton, whose intrusion was followed by the development of rifts and graben, mafic dike swarms, and eventually an Atlantic-type passive margin that signaled the beginning of a long period of tectonic quiescence and carbonate deposition for the NCC during Sinian times, which persisted into the Paleozoic. The style of tectonic accretion in the NCC changed at circa 2.5Ga, from an earlier phase of accretion of arcs that are presently preserved in horizontal lengths of several hundred kilometers, to the accretion and preservation of linear arcs several thousand kilometers long with associated oceanic plateaus, microcontinents, and accretionary prisms. The style of progressively younger and westward outward accretion of different tectonic components is reminiscent of the style of accretion in the Superior Craton, and may signal the formation of progressively larger landmasses at the end of the Archean (perhaps like the Kenorland Continent), then into the Paleoproterozoic, culminating in the assembly of the Columbia (Nuna) Continent at 1.9–1.8Ga.
Angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) are widely prescribed for primary hypertension (systolic blood pressure > 140 mmHg or diastolic ...blood pressure > 90 mmHg). However, while ACE inhibitors have been shown to reduce mortality and morbidity in placebo-controlled trials, ARBs have not. Therefore, a comparison of the efficacies of these two drug classes in primary hypertension for preventing total mortality and cardiovascular events is important.
To compare the effects of ACE inhibitors and ARBs on total mortality and cardiovascular events, and their rates of withdrawals due to adverse effects (WDAEs), in people with primary hypertension.
We searched the Cochrane Hypertension Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the World Health Organization (WHO) International Clinical Trials Registry Platform, and the ISI Web of Science up to July 2014. We contacted study authors for missing and unpublished information, and also searched the reference lists of relevant reviews for eligible studies.
We included randomized controlled trials enrolling people with uncontrolled or controlled primary hypertension with or without other risk factors. Included trials must have compared an ACE inhibitor and an ARB in a head-to-head manner, and lasted for a duration of at least one year. If background blood pressure lowering agents were continued or added during the study, the protocol to do so must have been the same in both study arms.
We used standard methodological procedures expected by The Cochrane Collaboration.
Nine studies with 11,007 participants were included. Of the included studies, five reported data on total mortality, three reported data on total cardiovascular events, and four reported data on cardiovascular mortality. No study separately reported cardiovascular morbidity. In contrast, eight studies contributed data on WDAE. Included studies were of good to moderate quality. There was no evidence of a difference between ACE inhibitors and ARBs for total mortality (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.88 to 1.10), total cardiovascular events (RR 1.07; 95% CI 0.96 to 1.19), or cardiovascular mortality (RR 0.98; 95% CI 0.85 to 1.13). Conversely, a high level of evidence indicated a slightly lower incidence of WDAE for ARBs as compared with ACE inhibitors (RR 0.83; 95% CI 0.74 to 0.93; absolute risk reduction (ARR) 1.8%, number needed to treat for an additional beneficial outcome (NNTB) 55 over 4.1 years), mainly attributable to a higher incidence of dry cough with ACE inhibitors. The quality of the evidence for mortality and cardiovascular outcomes was limited by possible publication bias, in that several studies were initially eligible for inclusion in this review, but had no extractable data available for the hypertension subgroup. To this end, the evidence for total mortality was judged to be moderate, while the evidence for total cardiovascular events was judged to be low by the GRADE approach.
Our analyses found no evidence of a difference in total mortality or cardiovascular outcomes for ARBs as compared with ACE inhibitors, while ARBs caused slightly fewer WDAEs than ACE inhibitors. Although ACE inhibitors have shown efficacy in these outcomes over placebo, our results cannot be used to extrapolate the same conclusion for ARBs directly, which have not been studied in placebo-controlled trials for hypertension. Thus, the substitution of an ARB for an ACE inhibitor, while supported by evidence on grounds of tolerability, must be made in consideration of the weaker evidence for the efficacy of ARBs regarding mortality and morbidity outcomes compared with ACE inhibitors. Additionally, our data mostly derives from participants with existing clinical sequelae of hypertension, and it would be useful to have data from asymptomatic people to increase the generalizability of this review. Unpublished subgroup data of hypertensive participants in existing trials comparing ACE inhibitors and ARBs needs to be made available for this purpose.
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